Staff View: Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides

Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting about 0.5–1.0% of the world population. Protein arginine deiminase type 4 (PAD4) is believed to be responsible for the occurrence of RA by catalyzing citrullination of proteins. The citrullinated proteins act as autoantigens b...

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Main Authors:	Ahmad Nadzirin, Izzuddin, Chor, Adam Leow Thean, Salleh, Abu Bakar, Abdul Rahman, Mohd Basyaruddin, Tejo, Bimo Ario
Format:	Article
Language:	English English
Published:	Elsevier Ltd. 2021
Subjects:	QD Chemistry RM Therapeutics. Pharmacology RM300 Drugs and their action
Online Access:	http://irep.iium.edu.my/92776/7/92776_Discovery%20of%20new%20inhibitor%20for%20the%20Protein%20Arginine%20Deiminase%20Type%204%20%28PAD4%29.pdf http://irep.iium.edu.my/92776/8/92776_Discovery%20of%20new%20inhibitor%20for%20the%20Protein%20Arginine%20Deiminase%20Type%204%20%28PAD4%29_Scopus.pdf http://irep.iium.edu.my/92776/ https://www.sciencedirect.com/science/article/abs/pii/S1476927121000542
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spelling	my.iium.irep.927762021-10-06T06:48:11Z http://irep.iium.edu.my/92776/ Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides Ahmad Nadzirin, Izzuddin Chor, Adam Leow Thean Salleh, Abu Bakar Abdul Rahman, Mohd Basyaruddin Tejo, Bimo Ario QD Chemistry RM Therapeutics. Pharmacology RM300 Drugs and their action Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting about 0.5–1.0% of the world population. Protein arginine deiminase type 4 (PAD4) is believed to be responsible for the occurrence of RA by catalyzing citrullination of proteins. The citrullinated proteins act as autoantigens by stimulating an immune response. Citrullinated α-enolase has been identified as one of the autoantigens for RA. Hence, α-enolase serves as a suitable template for design of potential peptide inhibitors against PAD4. The binding affinity of α-enolase-derived peptides and PAD4 was virtually determined using PatchDock and HADDOCK docking programs. Synthesis of the designed peptides was performed using a solid phase peptide synthesis method. The inhibitory potential of each peptide was determined experimentally by PAD4 inhibition assay and IC50 measurement. PAD4 assay data show that the N-P2 peptide is the most favourable substrate among all peptides. Further modification of N-P2 by changing the Arg residue to canavanine [P2 (Cav)] rendered it an inhibitor against PAD4 by reducing the PAD4 activity to 35% with IC50 1.39 mM. We conclude that P2 (Cav) is a potential inhibitor against PAD4 and can serve as a starting point for the development of even more potent inhibitors. Elsevier Ltd. 2021-04-23 Article PeerReviewed application/pdf en http://irep.iium.edu.my/92776/7/92776_Discovery%20of%20new%20inhibitor%20for%20the%20Protein%20Arginine%20Deiminase%20Type%204%20%28PAD4%29.pdf application/pdf en http://irep.iium.edu.my/92776/8/92776_Discovery%20of%20new%20inhibitor%20for%20the%20Protein%20Arginine%20Deiminase%20Type%204%20%28PAD4%29_Scopus.pdf Ahmad Nadzirin, Izzuddin and Chor, Adam Leow Thean and Salleh, Abu Bakar and Abdul Rahman, Mohd Basyaruddin and Tejo, Bimo Ario (2021) Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides. Computational Biology and Chemistry, 92. pp. 1-9. ISSN 1476-9271 https://www.sciencedirect.com/science/article/abs/pii/S1476927121000542 10.1016/j.compbiolchem.2021.107487
institution	Universiti Islam Antarabangsa Malaysia
building	IIUM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	International Islamic University Malaysia
content_source	IIUM Repository (IREP)
url_provider	http://irep.iium.edu.my/
language	English English
topic	QD Chemistry RM Therapeutics. Pharmacology RM300 Drugs and their action
spellingShingle	QD Chemistry RM Therapeutics. Pharmacology RM300 Drugs and their action Ahmad Nadzirin, Izzuddin Chor, Adam Leow Thean Salleh, Abu Bakar Abdul Rahman, Mohd Basyaruddin Tejo, Bimo Ario Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides
description	Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting about 0.5–1.0% of the world population. Protein arginine deiminase type 4 (PAD4) is believed to be responsible for the occurrence of RA by catalyzing citrullination of proteins. The citrullinated proteins act as autoantigens by stimulating an immune response. Citrullinated α-enolase has been identified as one of the autoantigens for RA. Hence, α-enolase serves as a suitable template for design of potential peptide inhibitors against PAD4. The binding affinity of α-enolase-derived peptides and PAD4 was virtually determined using PatchDock and HADDOCK docking programs. Synthesis of the designed peptides was performed using a solid phase peptide synthesis method. The inhibitory potential of each peptide was determined experimentally by PAD4 inhibition assay and IC50 measurement. PAD4 assay data show that the N-P2 peptide is the most favourable substrate among all peptides. Further modification of N-P2 by changing the Arg residue to canavanine [P2 (Cav)] rendered it an inhibitor against PAD4 by reducing the PAD4 activity to 35% with IC50 1.39 mM. We conclude that P2 (Cav) is a potential inhibitor against PAD4 and can serve as a starting point for the development of even more potent inhibitors.
format	Article
author	Ahmad Nadzirin, Izzuddin Chor, Adam Leow Thean Salleh, Abu Bakar Abdul Rahman, Mohd Basyaruddin Tejo, Bimo Ario
author_facet	Ahmad Nadzirin, Izzuddin Chor, Adam Leow Thean Salleh, Abu Bakar Abdul Rahman, Mohd Basyaruddin Tejo, Bimo Ario
author_sort	Ahmad Nadzirin, Izzuddin
title	Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides
title_short	Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides
title_full	Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides
title_fullStr	Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides
title_full_unstemmed	Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides
title_sort	discovery of new inhibitor for the protein arginine deiminase type 4 (pad4) by rational design of α-enolase-derived peptides
publisher	Elsevier Ltd.
publishDate	2021
url	http://irep.iium.edu.my/92776/7/92776_Discovery%20of%20new%20inhibitor%20for%20the%20Protein%20Arginine%20Deiminase%20Type%204%20%28PAD4%29.pdf http://irep.iium.edu.my/92776/8/92776_Discovery%20of%20new%20inhibitor%20for%20the%20Protein%20Arginine%20Deiminase%20Type%204%20%28PAD4%29_Scopus.pdf http://irep.iium.edu.my/92776/ https://www.sciencedirect.com/science/article/abs/pii/S1476927121000542
_version_	1713199562126000128
score	13.211869

Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides

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